Efficacy Endpoints of Radiation Therapy Group Protocol 0247: A Randomized, Phase 2 Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

Abstract

Purpose/Objectives Primary endpoint analysis of RTOG 0247 demonstrated preoperative RT with capecitabine plus oxaliplatin achieved a pCR pre-specified threshold (21%) to merit further study, whereas the RT with capecitabine plus irinotecan arm did not (10%). Secondary efficacy endpoints are reported here. Methods and Materials A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with two concurrent chemotherapy regimens: 1—capecitabine (1200 mg/m2/d M-F) plus irinotecan (50 mg/m2 /week × 4); and 2—capecitabine (1650 mg/m2/d M-F) plus oxaliplatin (50 mg/m2 /week × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4-8 weeks following chemoradiation, then 4-6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m2; leucovorin 400 mg/m2; 5FU 400 mg/m2; 5FU 2400 mg/m2) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms as each was evaluated individually. Results 104 patients (median age 57) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm are 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm are 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions Efficacy results for both arms are similar to other reported studies but suggest that pCR is an unsuitable surrogate for traditional survival metrics of clinical outcome. While it remains uncertain if the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest further study of irinotecan may be warranted.

Outcomes of neoadjuvant chemoradiotherapy in Japanese locally advanced rectal carcinoma patients

“…Similar results were obtained using neoadjuvant single-agent capecitabine plus radiotherapy for LARC [ 26 ]. Recently, cytotoxic agents such as irinotecan and oxaliplatin plus fluorouracil have been administrated for combination chemotherapy regarding NACRT [ 27 , 28 ]. Wong et al reported that the efficacy of capecitabine plus irinotecan with radiotherapy and the efficacy of capecitabine plus oxaliplatin with radiotherapy were similar in a neoadjuvant setting for LARC patients.…”

Long-term oncologic outcomes of neoadjuvant concurrent chemoradiotherapy with capecitabine and radical surgery in locally advanced rectal cancer: 10-year experiences at a single institution

“…Most recently, numerous studies reported short and long-term results of NCRT with combination of capecitabine, oxaliplatin, or bevacizumab. However, in many of those studies, the oncologic results were found to be not superior [ 21 22 ], and more significant toxicity and inferior compliance were reported, on the contrary [ 23 ]. Further research will be necessary to confirm that above-mentioned combinations of treatments could obtain more improved prognosis.…”

Total neoadjuvant therapy for rectal cancer: An emerging option

“…Other efforts are underway to intensify and improve the efficacy of neoadjuvant treatments. Particular emphasis has been placed on the role of improving the concurrent chemotherapy component of neoadjuvant CRT . To that end, a recently presented phase 2 clinical trial platform is aiming to identify novel sensitizing agents administered with neoadjuvant CRT that might improve disease‐related outcomes .…”

“…Particular emphasis has been placed on the role of improving the concurrent chemotherapy component of neoadjuvant CRT. 8,63,64 To that end, a recently presented phase 2 clinical trial platform is aiming to identify novel sensitizing agents administered with neoadjuvant CRT that might improve disease-related outcomes. 65 This platform will use a TNT approach, with neoadjuvant FOLFOX followed by CRT and then definitive surgery.…”